Substituted aminopropoxy-2-indolinones

ABSTRACT

THE PRESENT INVENTION CONCERNS NOVEL HETEROCYCLIC COMPOUNDS OF THE FORMULA:   1-R1,(R2-NH-CH2-CH(-OR3)-CH2-O-)-2-INDOLINONE   WHEREIN R1 IS HYDROGEN OR ALKYL, R2 IS A SUBSTITUTED OR UNSUBSTITUTED AROMATIC OR ALIPHATIC HYDROCARBON AND R3 IS HYDROGEN OR A CARBONYL SUBSTITUENT AND THE SIDE CHAIN IS IN THE 4 OR 7 POSITION OF THE OXINDOLE NUCLEUS. THE COMPOUNDS POSSESS PHARMACOLOGICAL PROPERTIES.

United States Patent 3,825,558 SUBSTITUTED AMINOPROPOXY-Z-INDOLINONES Fritz Seemann, Basel, Switzerland, assignor to Sandoz Ltd., Basel, Switzerland No Drawing. Filed June 19, 1972, Ser. No. 263,768 Claims priority, application Switzerland, June 24, 1971, 9,247/71, 9,248/71, 9,251/71 Int. Cl. C07d 27/40 US. Cl. 260-325 19 Claims ABSTRACT OF THE DISCLOSURE The present invention concerns novel heterocyclic compounds of the formula:

0R3 CHz-(ilEP-CHz-NHR:

wherein R is hydrogen or alkyl,

R is a substituted or unsubstituted aromatic or aliphatic hydrocarbon and R is hydrogen or a carbonyl substituent and the side chain is in the 4 or 7 position of the oxindole nucleus.

The compounds possess pharmacological properties.

The present invention relates to heterocyclic compounds and more specifically to substituted oxindoles.

The present invention provides compounds of formula I,

0 Rs CH1 HCHl NHR2 1 I wherein R is hydrogen or alkyl of 1 to 4 carbon atoms,

R is alkyl of 1 to 6 carbon atoms; cycloalkyl of 3 to 8 carbon atoms; alkoxyalkyl of 3 to 10 carbon atoms, the oxygen atom thereof being separated from the nitrogen atom by at least 2 carbon atoms; phenylalkyl of 8 to 12 carbon atoms; the phenyl being separated from the nitrogen atom by at least 2 carbon atoms; phenylalkyl of 8 to 12 carbon atoms, mono-substituted by alkyl of 1 to 5 carbon atoms or alkoxy of 1 to 5 carbon atoms, the phenyl being separated from the nitrogen atom by at least 2 carbon atoms; alkynyl of 2 to 7 carbon atoms; or carbalkoxyalkyl, the alkoxy substitnent thereof having 1 to 4 carbon atoms and the alkyl substituent thereof having 1 to 6 carbon atoms;

R is hydrogen, or COA, 6 wherein A is alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms substituted by alkyl of 1 to 4 carbon atoms, or a 5- or 6-membered oxygen-containing heterocycle, and the aminopropoxy side chain is in the 4 or 7 position of the oxindole nucleus.

When R is alkyl, representative examples are methyl, ethyl and n-propyl.

When R is alkyl of more than 2 carbon atoms, this is preferably branched, especially on the a carbon atom. Typical examples are, isopropyl, sec.butyl, tert.butyl, 3- pentyl and tert.pentyl.

Patented July 23, 1974 When R is phenylalkyl, representative examples are 3- phenylpropyl, l,1dimethyl-3-phenylpropyl and l-methyl- 3-phenylpropyl. When the phenyl is alkoxyor alkyl-substituted, particularly suitable substituents are methoxy as alkoxy substituent, as for example in 2-(4-methoxyphenyl)-1-methylethyl, and methyl as alkyl substituent.

When R is cycloalkyl, this is preferably of 3 to 6 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

When R is alkynyl, the triple bond is preferably situated in a position other than in an a-position to the nitrogen atom to which the alkynyl is bound. A preferred group of this series is inter alia 1,1-dimethyl-2-propynyl.

When R is carbalkoxyalkyl, particularly suitable examples of the alkoxy substituent are methoxy and ethoxy and the alkyl substituent is preferably branched in an a-position to the nitrogen atom to which it is bound. A preferred example of carbalkoxyalkyl is l-methyl-l-(methoxycarbonyl)ethyl.

When A is alkyl, this preferably contains 1 to 8 carbon atoms, particularly 1 to 4 carbon atoms.

When A is cycloalkyl substituted by alkyl, the preferred alkyl substituent is methyl. Preferred alkylated cycloalkyl groups are those which are monoalkylated in the l-position. A typical example of this series is l-methylcyclohexyl.

When A denotes a 5- or 6- membered, oxygen-containing heterocycle, this may, for example, be tetrahydropyranyl or furyl.

The present invention further provides a process for the production of a compound of formula I, comprising (a) reacting a compound of formula III,

III

wherein R is as defined above, and the epoxypropoxy side chain is in the 4 or 7 position of the oxindole nucleus, with an amine of formula IV,

H NR IV wherein R is as defined above, to obtain a compound of formula Ia,

uis

wherein R R and A are as defined above, and the aminopropoxy side chain is in the 4 to 7 position of the oxindole nucleus, or

(b) debenzylating a compound of formula V,

wherein R and R are as defined above, R is alkyl of 1 to -6 carbon atoms; cycloalkyl of 3 to 8 carbon atoms; alkoxyalkyl of 3 to 10 carbon atoms, the oxygen atom thereof being separated from the nitrogen atom by at least 2 carbon atoms; phenylalkyl of 8 to 12 carbon atoms, the phenyl being separated from the nitrogen atom by at least 2 carbon atoms; phenylalkyl of 8 to 12 carbon atoms mono-substituted by alkyl of 1 to carbon atoms or alkoxy of 1 to 5 carbon atoms, the phenyl being separated from the nitrogen atom by at least 2. carbon atoms; or carbalkoxyalkyl, the alkoxy substituent thereof having 1 to 4 carbon atoms and the alkyl substituent thereof having 1 t0 6 carbon atoms, and the aminopropoxy side chain is in the 4 or 7 position of the oxindole nucleus,

to obtain a compound of formula Ic,

The compounds of formula I may exist either in free base or acid addition salt forms. Acid addition salt forms may be produced from free base forms in manner known per se and vice versa.

The reaction of a compound of formula III with an amine of Formula IV may, for example, be effected in an inert organic solvent, e.g. an aromatic hydrocarbon such as benzene, toluene or xylene, a cyclic ether such as dioxane or tetrahydrofuran, or amyl alcohol.

The reaction temperature may range between 20 and 150 C.; the reaction is preferably effected at the boiling temperature of the reaction mixture at reflux. The reaction time is dependent on the reaction temperature.

Acylation of the resulting compound of formula Ia to obtain a compound of formula 1b is effected, for example, by adding an excess of an acid ACOOH, wherein A is as defined above, to a compound of formula Ia, and adding an excess of the corresponding anhydride to the resulting reaction mixture.

If desired, the reaction may be effected in an inert organic solvent, e.g. hexametapol, a chlorinated aliphatic hydrocarbon such as chloroform, or a cyclic or open chain ether such as dioxane.

The reaction temperature may range between room temperature and approximately 120 C. The reaction time is dependent on the reaction temperature.

After stirring for several hours, the reaction mixture may be worked up, e.g. by pouring it on ice, making it alkaline with lye or ammonia and extracting with a watermiscible inert organic solvent, e.g. ethyl acetate, a cyclic or open chain ether such as diethyl ether, or a chlorinated aliphatic hydrocarbon such as methyl chloride.

It will be appreciated that the working up stage should be effected with care to avoid splitting of the ester group. The addition of ACOQH may be omitted when the compound of formula Ia is used in the form of a salt with a suitable mineral acid, e.g. hydrochloric acid. The

, danger of an N-acylation may thus be eliminated by the protonization of the amino group of the aminopropoxy side chain; however, protonization is not essential especially when R is bound to the nitrogen atom by a tertiary carbon atom. When the reaction is effected in the presence of e.g. hydrogen chloride, the compound of formula Ib crystallizes in hydrochloride form, and working up of the reaction mixture is not necessary. Acylation may naturally likewise be effected with an acid halide. In this case the reaction is preferably effected at room temperature or at a slightly elevated temperature.

Debenzylation of a compound of formula V may, for example, be effected by hydrogenation in the presence of a catalyst, preferably a palladium catalyst in an inert organic solvent, e.g. ethyl acetate, or a cyclic or open chain ether such as diethyl ether, and is preferably effected at room temperature and normal pressure. After hydrogenation is complete, the catalyst is filtered off and the filtrate is evaporated to dryness.

The compounds of formulae III and V are new.

The compounds of formula III may, for example, be obtained by reaction of a salt, e.g. sodium salt, of the corresponding 4-hydroxy or 7-hydroxy oxindole with an epihalohydrin, e.g. epibromhydrin, conveniently in dimethyl sulphoxide as solvent. After the reaction is complete, working up may be effected by pouring the reaction mixture into water and extracting with ethyl acetate. The ethyl acetate extracts may be concentrated until the epoxypropoxy-oxindole crystallizes.

A compound of formula Va,

| R1 Va wherein R and R are as defined above, and the aminopropoxy side chain is in the 4 or 7 position of the oxindole nucleus, may be obtained in a manner analogous to the process for the production of compounds of formula Ia, by reaction of a compound of formula III with the corresponding benzylamine.

A compound of formula Vb,

OCOA R,

om-bnwm-fr-omQ 4 O l l wherein R R and A are as defined above, and the aminopropoxy side chain is in the 4- or 7-position of the oxindole nucleus, may be obtained by acylation of a compound of formula Va in analogous manner to that hereinbefore described for the production of compounds of formula Ib.

and thereapy of coronary diseases, particularly for the treatment of Angina pectoris, the hyperkinetic heart syndrome, conditions resulting from muscular hypertrophic subvalvular aortostenosis, and heart rhythm disorders, as indicated by (i) an inhibition in vitro of the positive inotropic adrenalin effect in the spontaneously beating quinea pig atrium when immersed in a buffer solution containing between 0.05 and 3 mg./ litre of the compound.

(ii) an inhibition of the tachycardia and hypotension caused by isoproterenol [1 (3,4 hydroxyphenyl)-2- isopropylaminoethanol] in the infusion test in the anesthetized cat on administration by infusion of an effective cumulative dose of between 0.1 and 1 mg. of the compound per kg. animal body weight, and

(iii) in the case of compounds of formula Ib a prolonged inhibition of the heart rate response to isoproterenol in the anesthetized and conscious dog on intravenous administration of between 0.125 and 1 mg. of the compound per kg. animal body weight.

For the abovementioned use, the dosage administered will, of course, vary depending upon the compound employed, mode of administration and treatment desired. However, in general, satisfactory results are obtained when administered at a daily dosage of between about 0.01 and mg./kg. animal body weight as a single dose. In the case of compounds of formula Ia, this dose may be administered as a divided dose two or three time daily or in retard form. In the case of compounds of formula Ib, this dose may, if necessary, be administered as a divided dose twice daily. For larger mammals, the total daily dosage for arenteral or oral administration is in the range of from about 1 to 500 mg., and unit dosage forms suitable for parenteral or oral administration comprise from about 0.3 to 500 mg. in the case of a compound of formula Ia, or from 0.2 to 500 mg. in the case of a compound of formula Ib, in the pharmaceutical composition incorporating a solid or liquid pharmaceutical carrier or diluent. The preferred mode of administration is oral administration. A suitable form of pharmaceutical composition for oral administration is a tablet.

Specific examples of daily doses for oral or parenteral administration and at which doses satisfactory results are obtained, are as follows viz:

(i) 4- (2-hydr0xy-3-isopropylaminopropoxy)oxindole, 0.01

to 0.2 mg./kg. animal body weight;

(ii) 4-(3-tert.butylamino 2 hydroxypropoxy)oxindo1e,

0.01 to 0.2 mg./ kg. animal body weight;

(iii) 4-[2-hydroxy 3 (2-methyl-3-butyn-2-ylamino)- propoxy]oxindole, 0.01 to 0.4 mg./kg. animal body weight;

(iv) 4-[3-(2-methyl 3 butyn-Z-ylamino)-2-pivaloyloxypropoxy]oxindole, 0.02 to 1 mg./kg. animal body weight; and

(v) 4-(3-tert.butylamino 2 pivaloyloxypropoxy)-oxindole, 0.1 to 0.4 mg./kg. animal body weight.

Free base and acid addition salt forms of the compounds of formula I exhibit the same type of activity. Examples of pharmaceutically acceptable acid addition salt forms are the hydrochloride, hydrogen oxalate and oxalate forms.

The preferred class of compounds are those wherein the aminopropoxy side chain is in the 4-position of the oxindole nucleus, particularly such compounds wherein R is hydrogen. A further preferred subclass of such compounds are those wherein R is alkyl of more than 2 carbon atoms and is branched, particularly at the a-POSitiOIl with respect to the nitrogen atom to which R is bound. Examples of specific preferred compounds are:

4-(2-hydroxy-3-isopropylaminopropoxy)oxindole,

4- 3-tert.butylamino-2-hydroxypropoxy)oxindole,

4-[2-hydroxy-3-(2-methyl-3-butyn 2 ylamino)propoxy] oxidole, 4-[3-(2-methyl-3-butyn 2 ylamino)-2-pivaloyloxypropoxy]oxindole and 4 (3-tert.butylamino-2- pivaloyloxy prop oxy) oxindole.

Examples of the present invention will now be described in more detail, wherein all temperatures referred to are in degrees Centigrade.

EXAMPLE 1 4-(2-Hydroxy-3-isopropylaminopropoxy)oxindole (free base form) [process (a)] 25.5 g. of 4-(2,3-epoxypropoxy)oxindole are taken up in 30 cc. of isopropylamine and cc. of dioxane, and the mixture is allowed to stand at room temperature for 24 hours. The reaction mixture is evaporated to dryness at reduced pressure, the evaporation residue is subsequently partitioned between ethyl acetate and l N tartaric acid, and the tartaric acid extracts are made alkaline while cooling with ice. Extraction is effected with methylene chloride, the organic phases are dried over magnesium sulphate and concentrated by evaporation at reduced pressure. The resulting basic portion is then chromatographed on 100 parts of basic silica gel with methylene chloride and 0.2 to 0.5% of methanol. The purified title compound is subsequently recrystallized from ethanol. M.P. -172".

The 4-(2,3-epoxypropoxy)oxindole, used as starting material, is produced as follows:

273 g. of 4-hydroxy-oxindole, 1300 cc. of dimethyl sulphoxide and 55.8 g. of 80% sodium hydride are heated to 60 for 1 /2 hours, a solution of 376 g. of epibromhydrin in 500 cc. of dimethyl sulphoxide is then added dropwise at room temperature and stirring is effected for 16 hours. The reaction solution is poured into water, extraction is effected with ethyl acetate, and the ethyl acetate extracts are concentrated until crystallization occurs. M.P. -177".

In analogous manner to that hereinbefore described in Example 1, the following compounds may be produced (free base form) viz:

1-methyl-4- [3- (p-n-pentoxyphenyl-n-hexylamino -propoxy] oxindole, 1-methyl-4- 3 m-n-p entylphenyl-n-hexylamino) -propoxy]oxindole and 4- [3 -n-butoxycarbonyl-n-hexylamino -propoxy] l-methyloxindole.

EXAMPLE 2 4-(3-tert.Butylamino-2-hydroxyprop0xy)oxindole (free base form) [process (a)] 2.0 g. of 4-(2,3-epoxypropoxy)oxindole, 6 cc. of tert.- butylamine and 50 cc. of dioxane are heated to the boil for 18 hours. The reaction solution is filtered whilst hot with the addition of some active charcoal and is then allowed to crystallize. The title compound has a M.P. of 197-198.

EXAMPLE 3 7-(2-Hydroxy-3-isopropylaminopropoxy)oxindole (free base form) [process (b)] The process is effected in a manner analogous to that described in Example 1, except that 7-hydroxy -oxindole is used in place of 4-hydroxy-oxindole, and benzyl isopropylamine is used in place of isopropylamine, and instead of etfecting the reaction at room temperature it is effected in an autoclave at 150 for 14 hours.

5 g. of the resulting 7-(3-benzylisopropylamino-Z-hydroxypropoxy)oxindole are taken up in 100 cc. of methanol, and shaking is effected with hydrogen in the presence of 5 g. of a palladium catalyst (5% of palladium on charcoal) until the uptake of hydrogen stops. The catalyst is filtered 01f, evaporation to dryness is effected at reduced pressure, and the title compound is crystallized from ethanol/ethyl acetate. M.P. 139-142.

7 EXAMPLE 4 4- 2-Hydroxy-3-isopropylaminopropoxy) -1-methyl oxindole (free base form) [process (a)] 7.7 g. of 4-hydroxy-1-methyl oxindole and 58 g. of epichlorhydrin are stirred in the presence of 0.45 cc. of piperidine at 80 for 48 hours. The excess epichlorhydrin is subsequently distilled off at reduced pressure, and the crude 4-(2,3-epoxypropoxy)-1-methyl oxindole obtained as oily residue is taken up in 100 cc. of dioxane and 50 cc. of isopropylamine, and heating is effected in an autoclave to 130 for 18 hours. The reaction solution is evaporated to dryness, and the residue is extracted between ethyl acetate and l N tartaric acid solution, the combined tartaric acid phases are made alkaline with 2 N caustic soda solution while cooling and are extracted with methylene chloride. After drying the methylene chloride extracts over magnesium sulphate and concentrating by evaporation at reduced pressure, the oily crude product is chromatographed on silica gel with methylene chloride saturated with ammonia and the addition of to of methanol, and the so purified title compound is recrystallized from ethyl acetate. M.P. 9698.

EXAMPLE 5' 4-[2-Hydroxy-3-(2-methyl-3-butyn-2-ylamino)propoxy] oxindole (free base form) [process (a)] 3 g. of 4-(2,3-epoxypropoxy)oxindole, 9 g. of 3-amino- 3-methyl butyne and cc. of tetrahydrofuran are heated to the boil while stirring for 2 days. The hot solution is filtered and is allowed to crystallize. The title compound has a M.P. of 172-174".

EXAMPLE 6 2-Methyl 2 [2 hydroxy 3 (4 oxindolyloxy)propylamino]propionic acid ethyl ester (free base form) [process (a)] The process is effected as described in Example 5, ex-. cept that a-aminoisobutyric acid ethyl ester is used in place of 3-amino-3-1nethyl butyne. The title compound crystallizes from ether. M.P. 158160.

EXAMPLE 7 4-[2-Hydroxy-3-(2-rnethyl-3-butyn-2-ylamino)propoxy] oxindole (free base form) [process (a)] The process is effected as described in Example 5, except that pure 4-(2,3-epoxypropoxy)oxindole is reacted with 3-amino-3-methyl butyne, whereby the title compound, having a M.P. of 172174, is obtained.

EXAMPLE 8 4- (3-tert.Butylamino-Z-hydroxypropoxy oxindole (free base form) [process (b)] 4.1 g. of 4-(2,3-epoxypropoxy)oxindole are reacted with 8.15 g. of benzyl tert.butylamine in cc. of dioxane in an autoclave at 150. The resulting 4-[3-(benzyl tert. butylamino) 2 hydroxypropoxy]oxindole (M.P. 141-143", from ethyl acetate) is debenzylated with hydrogen in 150 cc. of methanol and in the presence of 2.5 g. of a palladium catalyst (10% of palladium on charcoal) to obtain the title compound. M.P. 197198.

EXAMPLE 9 4-(3-Cyclopentylamino-Z-hydroxypropoxy)oxindole (free base form) [process (b)] 5 g. of 4-(2,3-epoxypropoxy) oxindole are taken up in 150 cc. of dioxane, and heating is effected with 6.4 g. of benzyl cyclopentylamine in an autoclave to 130 for 18 hours. The reaction solution is evaporated to dryness at reduced pressure, the residue is partitioned between ethyl acetate and 1 N tartaric acid solution, the tartaric acid phases are then made alkaline with 2 N caustic soda solution while cooling and are extracted with methylene chlo- 8 ride. The evaporation residue of the methylene chloride phase, which has been dried over magnesium sulphate, is crystallized from ether and yields 4-(3-benzylcyclopentylamino-Z-hydroxypropoxy)oxindole. M.P. 109111.

6.0 g. of the above base are debenzylated with hydrogen with 1.5 g. of a palladium catalyst (10% of palladium on charcoal) in 150 cc. of methanol. The title compound crystallizes from ethanol. M.P. 164-166".

EXAMPLE 10 4-{2-Hydroxy-3- [2- (4-methoxyphenyl ethylamino]propoxy} oxindole (free base form) [process (b)] The process is effected as described in Example 9, and the title compound, having a M.P. of 151153, from ethyl acetate, is obtained by debenzylation of 4-{N-benzyl- 2 hydroxy 3 [2 (4-methoxyphenyl)ethylamino]propoxy}oxindole (M.P. 106-113 from ethyl acetate/ ether) EXAMPLE l1 4-(3-Cyclopentylamino-2 heptanoyloxypropoxy)oxindole (hydrogen oxalate form) [process (a)] 2.5 g. of 4-(3-cyclopentylamino-Z-hydroxypropoxy) oxindole are heated to with 20.2 g. of enanthic acid and 2.7 g. of enanthic acid anhydride while stirring for 3 /2 hours. The reaction mixture is poured on ice and is made alkaline with 10% aqueous ammonia solution, extraction is effected with ether, the extracts are dried over magnesium sulphate, and the solvent is evaporated at reduced pressure. The resulting compound is converted into its hydrogen oxalate and is recrystallized from methanol. M.P. 182-185.

In analogous manner to that hereinbefore described in Example 11, the following compounds may be produced, (in hydrogen oxalate form) viz:

1-n-butyl-4- (2-dodecanoyloxy-3-n-hexanylaminopropoxy oxindole,

4-( 2-acetyloxy-3-cyclopropanylaminopropoxy)-l-sec.

butyl-oxindole,

, 4- 3-cyclohexylamino-2-cyclopropanoyloxypropoxy l-methyl oxindole,

4- (2-cyclohexanoyloxy-3 methoxyethylaminopropoxy) oxindole,

4- 3-n-heptoxy-n-propylamino-2-tetrahydropyranoyloxypropoxy) -1-methyl oxindole,

4- 2- 1-n-butylcyclohexanoyloxy) -3-phenylethylaminopropoxyJ-l-methyl oxindole,

4- 2- (Z-furancarbonyloxy -3-phenyl-n-hexylaminopropoxy]oxindole, and

1-sec.-butyl-4- Z-acetyloxy-3 ethynylaminopropoxy oxindole.

EXAMPLE 12 4-[3-Cyclopentylamino 2-(4-tetrahydropyranylcarbonyloxy)propoxy] oxindole (hydrogen oxalate form] [process (b)] A solution of 1.4 g. of 4-tetrahydropyrancarboxylic acid chloride in 20 cc. of dioxane is added dropwise while stirring to a solution of 1.2 g. of 4-(3-benzylcyclopentylamino-2-hydroxypr0poxy)oxindole and 0.42 g. of pyridine in 15 cc. of dioxane, and the reaction solution is subsequently heated to the boil for 4 /2 hours. The reaction solution is evaporated to dryness at reduced pressure, ice is added, and the solution is made alkaline with 10% aqueous ammonia solution, extraction is effected with ether, the extracts are dried over magnesium sulphate, and the solvent is evaporated at reduced pressure.

The 4-[3-benzylcyclopentylamino 2 (4-tetrahydropyranylcarbonyloxy)propoxy] oxindole obtained as an oil is debenzylated with hydrogen in the presence of 1 g. of a palladium catalyst (10% of palladium on charcoal) in 25 cc. of tetrahydrofuran. The resulting compound is converted into its hydrogen oxalate and crystallized from ethanol in druses. M.P. 168-171".

9 EXAMPLE 13 4-{3-[2-(4-Methoxyphenyl)ethylamino] 2-( l-methylcyclohexylcarbonyloxy)propoxy}oxindole (oxalate form) [process (b)] The process is eflFected as described in Example 12, using 4-{N-benzyl-2-hydroxy-3 [2-(4-methoxyphenyl) ethylamino]propoxy}oxindole as starting material, and 1-methyl-1-cyclohexanecarboxylic acid chloride, whereby the corresponding O-acylation product is obtained, which after debenzylation yields the free base form of the title compound, which is converted into its oxalate and crystallized from methanol. M.P. 182-185.

EXAMPLE 14 4-(3-tert.Butylamino-Z-pivaloyloxypropoxy)oxindole (oxalate form) [process (a)] 2.3 g. of 4-(3-tert.butylamino-2-hydroxypropoxy)oxindole are stirred at room temperature over night with 15 g. of pivalic acid and 1.7 g. of pivalic acid anhydride. The reaction solution is poured on ice and is made alkaline with aqueous ammonia solution, extraction is effected with ether, the extracts are dried over magnesium sulphate, and the solvent is evaporated at reduced pressure. The resulting compound is converted into its oxalate and is crystallized from ethanol/ethyl acetate. M.P. 230-232.

EXAMPLE 4-[3-(Z-Methyl-3-butyn-2-ylamino)-2-pivaloyloxypropoxy]oxindole (free base form) [process (a)] The title compound, which crystallizes from ether with a M.P. of 119-121", is obtained in a manner analogous to that described in Example 11 from 4-[2-hydroxy-3-(2- methyl-3-butyn-2-ylamino)propoxy]oxindole, the free base form being isolated.

The following compounds are obtained in a manner analogous to that described in Example 1:

7-(2-hydroxy-3 isopropylaminopropoxy)oxindole (free base form), M.P. 139-142, by reaction of 7-(2,3- epoxypropoxy)oxindole with isopropylamine;

4- 3-cyclopentylamino -2-hydroxypropoxy) oxindole (free base form), M.P. 164-166, by reaction of 4-(2,3- epoxypropoxy)oxindole with cyclopentylamine;

4-{2-hydroxy-3-[2-(4 methoxyphenyl)ethylamino]propoxy}oxindole (free base form), M.P. 151-153, by reaction of 4-(2,3-epoxypropoxy)oxindole with 2-(4-methoxyphenyl) ethylamine.

The following compounds are obtained in a manner analogous to that described in Example 3:

4-(2-hydroxy-3 isopropylaminopropoxy)oxindole (free base form), M.P. 170-172, by debenzylation of 4-(3- benzylisopropylamino-2-hydroxypropoxy oxindole;

4-(2-hydroxy-3 isopropylaminopropoxy)-1-methyl oxindole (free base form), M.P. 96-98, by debenzylation of 4-(3-benzylisopropylamino 2-hydroxypropoxy)-1- methyl oxindole;

2-methyl-2-[2-hydroxy-3- (4 oxindolyloxy)propylamino] propionic acid ethyl ester (free base form), M.P. 15 8- 160", by debenzylation of 2-methyl Z-{N-benzyl-[Z-hydroxy-3-(4-oxindolyloxy) propylamino}propionic acid ethyl ester.

Proceeding in the manner analogous to that described in Example 11, including conversion to the specified acid addition salt form,

4-[3-cyclopentylamino-2 (4 tetrahydropyranylcarbonyloxy)propoxy]oxindole (hydrogen oxalate form), M.P. 168-171, is obtained by acylation of 4-(3-cyclopentylamino-2-hydroxyprop oxy) oxindole;

4-{3-[2 (4 methoxyphenyl)ethylamino] 2-(1-methylcyclohexylcarbonyloxy)propoxy}oxindole (oxalate form), M.P. 182-185, is obtained by acylation of 4- 10 {2-hydroxy-3[2-(4 methoxyphenyl)ethylamino]pro poxy}oxindole.

Proceeding in the manner analogous to that described in Example 13, including conversion to the specific acid 5 addition salt form,

4 (3-cyclopentylamino-Z-heptanoyloxypropoxy)oxindole hydrogen oxalate form), M.P. 182-185, is obtained by debenzylation of 4-(3-benzylcyclopentylamino-Z-heptanoyloxypropoxy)oxindole;

4-(3-tert.-butylamino 2 pivaloyloxypropoxy)oxindole (hydrogen oxalate form), M.P. 116 (decomp.), is ob tained by debenzylation of 4-(3-benzyl tert.butylamino- 2-pivaloyloxypropoxy)oxindole.

STARTING MATERIALS The 4-[2-hydroxy 3 (2-methyl-3-butyn-2-ylamino)- propoxy1oxindole used as a starting material may, for example, be obtained as follows:

2O 3 g. of 4(2,3-epoxypropoxy)oxindole, 9 g. of 3-amino-3- methyl butyne and cc. of tetrahydrofuran are heated to the boil while stirring for 2 days. The hot solution is filtered and is allowed to crystallize. 4-[2-Hydroxy-3- (2 methyl-3-butyn-2-ylamino)propoxy]oxindole, hav- 25 ing a M.P. of 172-174, is obtained.

What is claimed is: 1. A compound of the formula:

R is alkyl of 1 to 6 carbon atoms; cycloalkyl of 3 to 8 carbon atoms; alkoxyalkyl of 3 to 10 carbon atoms, the oxygen atom thereof being separated from the nitrogen atom by at least 2 carbon atoms; phen ylalkyl of 8 to 12 carbon atoms, the phenyl being separated from the nitrogen atom by at least 2 carbon atoms; phenylalkyl of 8 to 12 carbon atoms mono-substituted by alkyl of 1 to 5 carbon atoms or alkoxy of 1 to 5 carbon atoms, the phenyl being separated from the nitrogen atom by at least 2 carbon atoms; alkynyl of 2 to 7 carbon atoms; or carbalkoxyalkyl, the alkoxy substituent thereof having 1 to 4 carbon atoms and the alkyl substituent thereof having 1 to 6 carbon atoms;

R is hydrogen; or -COA, wherein A is alkyl of l to 12 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms substituted by alkyl of 1 to 4 carbon atoms, or a 5- or 6-membered oxygen heterocycle having one oxygen atom; and the aminopropoxy side chain is in the 4 or 7 position of the oxindole nucleus,

in free base or pharmaceutically acceptable acid addition salt form.

2. A compound of Claim 1, wherein R is COA, where in A is as defined in Claim 1.

3. A compound of Claim 1, wherein R is hydrogen or methyl, R is i-propyl, tert.butyl, cyclopentyl, pmethoxyphenylethyl, 2-methyl-3-butyn-2-yl or 2-ethoxycarbonyl-propan-Z-yl, and R is hydrogen, pivaloyl, heptanoyl, tetrahydropyranyl 2 carbonyl or l-methylcyclohexylcarbonyl.

4. A compound of Claim 1, wherein R is alkyl and is branched at the a-position with respect to the nitrogen atom to which it is bonded.

5. A compound of Claim 1, wherein R is hydrogen.

6. A compound of Claim 1, wherein the aminopropoxy I side chain is in the 4-position of the oxindole nucleus.

7. The compound of Claim 1, which is 4-(2-hydroxy- 3-isopropylaminopropoxy)oxindole.

8. The compound of Claim 1, which is 4-(3-tert.butylamino-Z-hydroxypropoxy)oxindole.

9. The compound of Claim 1, which is 7-(2-hydroxy-3- isopropylaminopropoxy)oxindole.

10. The compound of Claim 1, which is 4-(2-hydroxy- 3-isopropylaminopropoxy)-1-methy1 oxindole.

11. The compound of Claim 1, which is 4-[2-hydroxy- 3- 2-methyl-3-butyn-2-ylamino propoxy] oxindole.

12. The compound of Claim 1, which is 2-methyl-2- [2-hydroxy 3 (4-oxindolyloxy)propylamino]propionic acid ethyl ester.

13. The compound of Claim 1, which is 4-(3-cyclopentylamino-2-hydroxypropoxy oxindole 14. The compound of Claim 1, which is 4- [Z-hydroxy- 3- [2- 4-methoxyphenyl ethylamino] propoxy] oxindole.

15. The compound of Claim 1, which is 4-(3-cyclopentylamino-2-heptanoyloxypropoxy oxindole 16. The compound of Claim 1, which is 4-[3-cyclopentylamino-Z (4 tetrahydropyranylcarbonyloxy)propoxy] oxindole.

17. The compound of Claim 1, which is 4-{3-[2-(4- methoxyphenyl)ethylamino] 2 lmethylcyclohexylcarbonyloxy)propoxy}oxindole.

18. The compound of Claim 1, which is 4-(3-tert.butylamino-2-pivaloyloxypr0poxy oxindole.

19. The compound of Claim 1, which is 4-[3-(2-methyl-3-butyn-2-ylamino -2-pivaloyloxypropoxy] oxindole.

References Cited UNITED STATES PATENTS 3,705,907 12/1972 Troxler 260326.l4 R

JOSEPH A. NARCAVAGE, Primary Examiner US. Cl. X.R. 424274 

